Abstract Recent evidence has confirmed that positive energy balance, as estimated by obesity, strongly influences prostate carcinogenesis. However, the complexity of how energy balance influences, and is influenced, by various metabolic hormones and sympathetic nervous system activity (SNS) adds considerable complexity to the role of energy balance for this cancer. Further, the influences of energy balance may differ for prostate cancer incidence and progression. A third complicating factor is that there may be distinct etiologies for early- onset and late-onset prostate cancers. We propose three distinct patterns, suggested by our preliminary data and other studies, whereby energy balance related variables influence prostate cancer: Pattern 1: Metabolic alterations associated with obesity and lack of physical activity, including high insulin and leptin, and low adiponectin levels, increase risk of prostate cancer progression. Further, the low testosterone levels associated with obesity may contribute to more poorly differentiated cancers and thus a worse prognosis. Pattern 2: Higher insulin-like growth factor (IGF-1) levels influence progression of well- to moderately-well differentiated prostate cancers, whereas cancers that have molecular alterations in the IGF-1 signaling pathway and hence upregulated IGF-1 signaling are relatively unresponsive to circulating IGF-1 levels. Pattern 3: Younger men with an inherent metabolic phenotype related to SNS activity that disassociates high energy intake from weight gain and which is associated with chronic prostatitis/chronic pelvic pain syndrome prostatitis are at increased risk of prostate cancer. We will address these three patterns whereby energy balance may influence prostate cancer risk in the Health Professionals Follow-up Study (HPFS), a cohort of the 47,000 men free of cancer at baseline in 1986. We project 6,085 new cases of prostate cancer by 2010, including 668 fatal cases, with tumor blocks from over 1,900 prostatectomy cases. The sources of the exposure data in the HPFS are questionnaire, including diet, anthropometric measures, activity, medication use, and plasma samples. The outcome data will be based on (1) medical record and pathology report review, and (2) tissue block markers that correlate with disease progression. Stratified analysis and multivariate analysis will be used to control for confounding factors. Our ultimate goal is to better understand how body weight, and related dietary and other modifiable factors, influence prostate carginogenesis at various stages.